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Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer

The BRAF V600E mutation causes impaired expression of sodium iodide symporter (NIS) and radioiodine refractoriness of thyroid cancer, but the underlying mechanism remains undefined. In this study, we hypothesized that histone deacetylation at the NIS (SLC5A5) promoter was the mechanism. Using the ch...

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Autores principales: Zhang, Zongjing, Liu, Dingxie, Murugan, Avaniyapuram Kannan, Liu, Zhimin, Xing, Mingzhao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Bioscientifica Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920838/
https://www.ncbi.nlm.nih.gov/pubmed/24243688
http://dx.doi.org/10.1530/ERC-13-0399
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author Zhang, Zongjing
Liu, Dingxie
Murugan, Avaniyapuram Kannan
Liu, Zhimin
Xing, Mingzhao
author_facet Zhang, Zongjing
Liu, Dingxie
Murugan, Avaniyapuram Kannan
Liu, Zhimin
Xing, Mingzhao
author_sort Zhang, Zongjing
collection PubMed
description The BRAF V600E mutation causes impaired expression of sodium iodide symporter (NIS) and radioiodine refractoriness of thyroid cancer, but the underlying mechanism remains undefined. In this study, we hypothesized that histone deacetylation at the NIS (SLC5A5) promoter was the mechanism. Using the chromatin immunoprecipitation approach, we examined histone acetylation status on the lysine residues H3K9/14, H3K18, total H4, and H4K16 at the NIS promoter under the influence of BRAF V600E. We found that expression of stably or transiently transfected BRAF V600E inhibited NIS expression while the deacetylase inhibitor SAHA stimulated NIS expression in PCCL3 rat thyroid cells. Although BRAF V600E enhanced global histone acetylation, it caused histone deacetylation at the NIS promoter while SAHA caused acetylation in the cells. In human thyroid cancer BCPAP cells harboring homozygous BRAF V600E mutation, BRAF V600E inhibitor, PLX4032, and MEK inhibitor, AZD6244, increased histone acetylation of the NIS promoter, suggesting that BRAF V600E normally maintained histone in a deacetylated state at the NIS promoter. The regions most commonly affected with deacetylation by BRAF V600E were the transcriptionally active areas upstream of the translation start that contained important transcription factor binding sites, including nucleotides −297/−107 in the rat NIS promoter and −692/−370 in the human NIS promoter. Our findings not only reveal an epigenetic mechanism for BRAF V600E-promoted NIS silencing involving histone deacetylation at critical regulatory regions of the NIS promoter but also provide further support for our previously proposed combination therapy targeting major signaling pathways and histone deacetylase to restore thyroid gene expression for radioiodine treatment of thyroid cancer.
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spelling pubmed-39208382014-04-01 Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer Zhang, Zongjing Liu, Dingxie Murugan, Avaniyapuram Kannan Liu, Zhimin Xing, Mingzhao Endocr Relat Cancer Research The BRAF V600E mutation causes impaired expression of sodium iodide symporter (NIS) and radioiodine refractoriness of thyroid cancer, but the underlying mechanism remains undefined. In this study, we hypothesized that histone deacetylation at the NIS (SLC5A5) promoter was the mechanism. Using the chromatin immunoprecipitation approach, we examined histone acetylation status on the lysine residues H3K9/14, H3K18, total H4, and H4K16 at the NIS promoter under the influence of BRAF V600E. We found that expression of stably or transiently transfected BRAF V600E inhibited NIS expression while the deacetylase inhibitor SAHA stimulated NIS expression in PCCL3 rat thyroid cells. Although BRAF V600E enhanced global histone acetylation, it caused histone deacetylation at the NIS promoter while SAHA caused acetylation in the cells. In human thyroid cancer BCPAP cells harboring homozygous BRAF V600E mutation, BRAF V600E inhibitor, PLX4032, and MEK inhibitor, AZD6244, increased histone acetylation of the NIS promoter, suggesting that BRAF V600E normally maintained histone in a deacetylated state at the NIS promoter. The regions most commonly affected with deacetylation by BRAF V600E were the transcriptionally active areas upstream of the translation start that contained important transcription factor binding sites, including nucleotides −297/−107 in the rat NIS promoter and −692/−370 in the human NIS promoter. Our findings not only reveal an epigenetic mechanism for BRAF V600E-promoted NIS silencing involving histone deacetylation at critical regulatory regions of the NIS promoter but also provide further support for our previously proposed combination therapy targeting major signaling pathways and histone deacetylase to restore thyroid gene expression for radioiodine treatment of thyroid cancer. Bioscientifica Ltd 2014-04 /pmc/articles/PMC3920838/ /pubmed/24243688 http://dx.doi.org/10.1530/ERC-13-0399 Text en © 2014 The authors http://creativecommons.org/licenses/by/3.0/deed.en_GB This work is licensed under a Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/deed.en_GB)
spellingShingle Research
Zhang, Zongjing
Liu, Dingxie
Murugan, Avaniyapuram Kannan
Liu, Zhimin
Xing, Mingzhao
Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer
title Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer
title_full Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer
title_fullStr Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer
title_full_unstemmed Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer
title_short Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer
title_sort histone deacetylation of nis promoter underlies braf v600e-promoted nis silencing in thyroid cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920838/
https://www.ncbi.nlm.nih.gov/pubmed/24243688
http://dx.doi.org/10.1530/ERC-13-0399
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